Pulmonary emphysema is a prevalent lung disease with no effective treatment. Its unique features are the ultimate disappearance of lung tissue and loss of alveoler-capillary units. The lung destruction becomes sustained and progressive even long after discontinuation of smoking. Only recently, investigations (e.g., via inhibition of vascular endothelial growth factor receptor, VEGFR-inh) have uncovered a critical role for apoptosis in emphysema pathogenesis, in conjunction with oxidative stress and matrix protease activation, all of which synergize, triggering alveolar destruction. Key to developing treatments for emphysema patients is identifying the molecular mechanisms that trigger, amplify, and sustain alveolar cell destruction. Ceramide, a signaling sphingolipid, is now known to be a critical mediator of apoptosis in different organs. We recently demonstrated that ceramide is a key mediator of lung apoptosis and emphysema in the established VEGFR- inh model of emphysema in both mice and rats. Moreover, we developed cutting-edge approaches to quantify ceramide and its fatty acid profile and report striking increases in its different molecular species in the lungs of emphysema patients. Together with evidence linking ceramide with oxidative stress and protease induction, these data firmly position ceramide as a novel and potentially key mediator of multiple processes linked to emphysema pathogenesis. Therefore, we hypothesize that an imbalanced, upregulated ceramide signaling triggers mechanisms that cause and amplify the alveolar destruction in emphysema. These mechanisms, hereby named "destructive pathways", involve lung cell apoptosis, oxidative stress, and matrix proteolysis. In Specific Aim (SA) #1 we will investigate whether ceramide upregulation is necessary and sufficient to trigger emphysema. We will utilize the VEGFR-inh model and inhibit ceramide by pharmacologic, and molecular (acid sphingomyelinase and serine-palmitoyl transferase SiRNA) strategies. In SA #2 we will identify the mechanisms by which ceramide self-amplifies its synthesis, thereby triggering a further, paracrine level of amplification of alveolar destruction. Finally, SA #3 will propose that restoring the balance of sphingolipid signaling of the pro-apoptotic ceramide vs. pro-survival sphingosine-1-P will block alveolar apoptosis and thus emphysema. Once understood, the molecular dis-regulation of ceramide could offer a target for treatments and/or prevention of emphysema.